WO1997020810A1 - Process for the preparation of 1-aryl-1-cyanocyclobutane derivatives - Google Patents

Process for the preparation of 1-aryl-1-cyanocyclobutane derivatives Download PDF

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Publication number
WO1997020810A1
WO1997020810A1 PCT/EP1996/005246 EP9605246W WO9720810A1 WO 1997020810 A1 WO1997020810 A1 WO 1997020810A1 EP 9605246 W EP9605246 W EP 9605246W WO 9720810 A1 WO9720810 A1 WO 9720810A1
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WO
WIPO (PCT)
Prior art keywords
formula
dimethyl sulphoxide
carbon atoms
compound
temperature
Prior art date
Application number
PCT/EP1996/005246
Other languages
English (en)
French (fr)
Other versions
WO1997020810A8 (en
Inventor
Stephen John Barker
Sharon Michelle Clark
Original Assignee
Knoll Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to SI9630254T priority Critical patent/SI0863868T1/xx
Priority to DE69611835T priority patent/DE69611835T2/de
Priority to PL96326926A priority patent/PL185047B1/pl
Priority to IL12434196A priority patent/IL124341A/en
Priority to EP96941602A priority patent/EP0863868B1/en
Priority to US09/077,698 priority patent/US6545173B1/en
Priority to KR1019980704120A priority patent/KR19990071838A/ko
Application filed by Knoll Aktiengesellschaft filed Critical Knoll Aktiengesellschaft
Priority to BR9611683A priority patent/BR9611683A/pt
Priority to NZ323896A priority patent/NZ323896A/xx
Priority to DK96941602T priority patent/DK0863868T3/da
Priority to AT96941602T priority patent/ATE199247T1/de
Priority to SK626-98A priority patent/SK282470B6/sk
Priority to AU10939/97A priority patent/AU717603B2/en
Priority to JP9520945A priority patent/JP2000501402A/ja
Publication of WO1997020810A1 publication Critical patent/WO1997020810A1/en
Priority to BG102473A priority patent/BG63498B1/bg
Priority to NO982474A priority patent/NO309265B1/no
Publication of WO1997020810A8 publication Critical patent/WO1997020810A8/en
Priority to GR20010400419T priority patent/GR3035572T3/el

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring

Definitions

  • the present invention relates to an improved process for the preparation of arylcyclobutyl cyanides.
  • 1-(4-Chlorophenyl)cyclobutyl cyanide is an intermediate useful for the preparation of sibutramine, N-1-[1-(4-chlorophenyl)cyclobutyl]-3- methylbutyl-N,N-dimethylamine.
  • Sibutramine is useful in the treatment of depression, Parkinson's disease, obesity, Non Insulin Dependent Diabetes Mellitus (NIDDM) and epilepsy.
  • 1-(4-Chlorophenyl)cyclobutyl cyanide was prepared by reacting 4- chlorophenylacetonitrile with 1 ,3-dibromobutane in a mixture of dimethyl sulphoxide and ether at 25-35°C using sodium hydride as the base (J.Org. Chem. 36 (9), 1308, 1971). It is also disclosed that the process is effective if the mineral oil is removed from the sodium hydride by washing with toluene and then adding a slurry of sodium hydride in toluene to the dimethyl sulphoxide. Similar preparations are also described in US4.235.926, US3.526.656. US4.348.409, US5,405,866 and J.Organomet. Chem. 448, 1-2, p9-14(1993). The yields quoted vary between 43% and 78%.
  • GB2098602A discloses a process for the preparation of 1-(4- chlorophenyl)cyclobutyl cyanide comprising the reaction of 4-chlorophenyl- acetonitrile with a 1 ,3-dibromopropane in the presence of sodium hydride (dispersed in mineral oil). The reaction is described as being carried out in dry dimethyl sulphoxid ⁇ under nitrogen with stirring initially at room temperature, then at a temperature in the range 30 to 35°C for 2 hours. This preparation is also reported in EP 191542 and GB 2127819. The presence of dimethyl sulphoxide in the aqueous waste from these processes renders the waste ineligible for discharge to the chemical effluent drain of chemical production plants. The waste therefore has to be specially disposed of. This leads to high production costs and adverse environmental effects (more resources and energy are required to enable safe disposal of the aqueous waste). It is therefore desirable to find a process which does not require dimethyl sulphoxide.
  • WO95/00489 describes a process for producing 1-(2-pyridyl)cyclopropyl cyanide This reaction was carried out in toluene using a 50% aqueous sodium hydroxide solution as the base. The base was added to a stirred mixture of 2-(2- pyridyl)acetonitrile, l-bromo-2-chloroethane, benzyltriethylammonium chloride and toluene at 25°C. The mixture was then heated at 70-75°C for 2 hours. The product was extracted into ether and isolated in good yield (-85%). A disadvantage of this process is the presence of water in the initial reaction. This can lead to a rather high level of impurity formation.
  • the present invention provides a process for the preparation of compounds of formula I
  • R, and R 2 which may be the same or different, are H, halo, trifluoromethyl, an alkyl group containing 1 to 3 carbon atoms, an alkoxy or alkylthio group containing 1 to 3 carbon atoms, phenyl, or R, and R 2 , together with the carbon atoms to which they are attached, form a second benzene ring which may be substituted by one or more substituents selected from halo, an alkyl group containing 1 to 4 carbon atoms, an alkoxy group containing 1 to 4 carbon atoms, or the substituents of the second benzene ring together with the two carbon atoms to which they are attached may form a further benzene ring;
  • said process comprising the reaction of a 1 ,3-dihalopropane, a compound of formula " in which RT and R 2 are as defined above, and a suspension of a base in a substantially dimethyl sulphoxide-free solvent at a temperature of at least 35°C.
  • a preferred process according to the present invention provides a process for the preparation of compounds of formula I as defined by formula III
  • R 1 and R 2 are as defined above, and a suspension of a base in a substantially dimethyl sulphoxide-free solvent at a termperature of at least 35°C.
  • a more preferred process according to the present invention provides a process for the preparation of compounds of formula IV in which Ri represents chloro and R 2 represents hydrogen or chloro comprising the reaction of a 1,3- dihalopropane, a compound of formula IV in which R 1 represents chloro and R 2 represents hydrogen or chloro, respectively, and a suspension of a base in a substantially dimethyl sulphoxide-free solvent at a temperature of at least 35°C.
  • the more preferred processes of the present invention provide a) a process for the preparation of 1-(4-chlorophenyl)cyclobutyl cyanide comprising the reaction of a 1 ,3-dihalopropane, 4-chlorophenylacetonitrile and a suspension of a base in a substantially dimethyl sulphoxide-free solvent at a temperature of at least 35°C; and b) a process for the preparation of 1-(3,4-dichlorophenyl)cyclobutyl cyanide and a suspension of a base in a substantially dimethyl sulphoxide-free solvent at a temperature of at least 35°C.
  • a most preferred process of the present invention provides a process for the preparation of 1-(4-chlorophenyl)cyclobutyl cyanide comprising the reaction of a 1 ,3- dihalopropane, 4-chlorophenylacetonitrile and a suspension of a base in a substantially dimethyl sulphoxide-free solvent at a temperature of at least 35°C.
  • the process comprises the addition of a solution of a 1,3- dihalopropane and a compound of formula II in a substantially dimethyl sulphoxide- free solvent to a suspension of a base in a substantially dimethyl sulphoxide-free solvent at a temperature of at least 35°C.
  • solvent defines a water-immiscible liquid which is capable of keeping the 1 ,3-dihalopropane and the 4-chlorophenylacetonitrile in solution at the reaction temperature.
  • the use of a water-immisicible liquid is advantageous as the work-up procedure is simplified and therefore process costs are reduced.
  • substantially dimethyl sulphoxide-free means that no more than 5% of dimethyl sulphoxide is present in the solvent, preferably no more than 2%, and most preferably there is a complete absence of dimethyl sulphoxide.
  • the dimethyl sulphoxide-free solvent is a water immiscible organic liquid, preferably the liquid is non-polar. More preferably, the dimethyl sulphoxide- free solvent is a hydrocarbon such as toluene or petroleum ether. Most preferably the dimethyl sulphoxide-free solvent is toluene.
  • the base is potassium hydroxide or sodium hydroxide.
  • the amount of base present is at least 2 molar equivalents relative to the amount of the compound of formula II present. More preferably, the amount is in the range of 3.8 to 4.7 molar equivalents relative to the amount of the compound of formula II present.
  • the suspension of base is preferably maintained by agitation such as stirring, shaking, or bubbling an inert gas, such as nitrogen, through the solvent, but any other means of maintaining a suspension may also be used.
  • agitation such as stirring, shaking, or bubbling an inert gas, such as nitrogen, through the solvent, but any other means of maintaining a suspension may also be used.
  • an inert gas such as nitrogen
  • it is a stirred suspension.
  • reaction is carried out under an inert atmosphere such as nitrogen.
  • phase-transfer catalyst present in the suspension of the base.
  • the phase transfer catalyst is a quaternary salt or a crown ether.
  • the catalyst is selected from one of the following: butylpyridinium bromide, tetrabutylammonium bisulphate, benzyltriethylammonium bromide, benzyltriethylammonium chloride, benzyltrimethylammonium chloride, benzyltrimethylamrnonium fluoride, hexadecyltriethylammonium bromide, hexadecyltriethylphosphonium bromide, hexadecyltrimethylammonium bromide, hexadecyltrimethylammonium chloride, dibutyldimethylammonium chloride, decyltriethylammonium bromide, hexadecyttributylphosphon
  • phase transfer catalyst is a quaternary ammonium salt or a crown ether.
  • phase-transfer catalyst is tetra-n-butylammonium bromide, tetra-n- butylammonium hydrogen sulphate, or tetra-n-butylammonium iodide.
  • the amount of phase-transer catalyst present is in the range of 0.01 to 0.2 molar equivalents relative to the amount of the compound of formula II present. More preferably the amount is in the range of 0.05 to 0.15 molar equivalents relative to the amount of the compound of formula II present.
  • the temperature is in the range 35-80°C, more preferably in the range 35.1-69°C, most preferably in the range 40-60°C.
  • water is added to aid stirring when the addition is 60-85% complete, more preferably 75% complete.
  • the volume of water added is in the range of 0 to 5.0 parts by weight relative to the weight of the compound of formula II present.
  • the volume of water added is in the range of 0 to 1.0 parts of weight relative to the weight of the compound of formula II present. More preferably the volume of water added is on the range of 0.7 to 0.9 parts by weight relative to the weight of the compound of formula II present.
  • the reaction is quenched by the addition of water.
  • the reaction is carried out at atmospheric pressure.
  • the 1 ,3-dihalopropane is 1 ,3-dibromopropane, 1 ,3-dichloropropane or 1-bromo-3-chloropropane.
  • the 1 ,3-dihalopropane is 1 ,3- dibromopropane.
  • the amount of 1 ,3-dihalopropane used is in the range of 0.8 to 1.5 molar equivalents relative to the amount of the compound of formula II present.
  • the amount of 1 ,3-dihalopropane used is in the range of 0.9 to 1.2 molar equivalents relative to the amount of the compound of formula II present.
  • the amount of 1 ,3-dihalopropane used is in the range .0 to 1.05 molar equivalents relative to the amount of the compound of formula II present.
  • a further advantage of the present invention is that it may avoid the need for isolation of 1-(4-chlorophenyl)cyclobutyl cyanide when it is desired to obtain sibutramine. Instead it may be possible to use the toluene solution of 1-(4- chlorophenyl)cyclobutanecarbonitrile immediately in the reaction described in GB2098602A, inco ⁇ orated herein by reference.
  • the process comprises the addition of a solution of 1 ,3-dibromopropane and 4-chlorophenylacetonitrile in toluene to a stirred suspension of powdered potassium hydroxide with tetra-n- butylammonium bromide in toluene at a temperature in the range 35-80°C, preferably in the range 35.1 -69°C, more preferably in the range 40-60°C. Water is added after 60-85% completion of the addition. The reaction is quenched by the addition of water.
  • the invention is illustrated by the following Examples which are given by way of example only.
  • the final product of each of these Examples was characterised by one or more of the following procedures: gas-liquid chromatography; high performance liquid chromatography; elemental analysis; nuclear magnetic resonance spectroscopy and infrared spectroscopy.
  • the organic phase was separated and stirred with water (354 ml) and caustic soda (76 g) at f°C for 15 minutes, then allowed to settle.
  • the organic layer was separated, then stirred at f°C with water (300 ml) and concentrated hydrochloric acid (20 ml), the aqueous layer having a pH of 3 or less.
  • the organic layer was separated, then stirred with water (300 ml) at f°C for 15 minutes and the organic layer separated. This was repeated until the aqueous layer had a pH between 6 and 8.
  • TBAHS tetra-n-butylammonium hydrogen sulphate.
  • Temperatures d°C and f°C are the same for Examples 1-10.
  • TBAHS tetra-n-butylammonium hydrogen sulphate
  • TBAB means tetra-n-butylammonium bromide
  • TBAHS means tetra-n-butylammonium hydrogen sulphate
  • DMSO means dimethyl sulphoxide
  • the reaction is then quenched by addition of water (254 ml) over 15 minutes at 60°C, and the mixture stirred for 20 minutes.
  • the organic phase is separated and stirred with water (354 ml) and caustic soda (76 g) at 60°C for 15 minutes, then allowed to settle.
  • the organic layer is separated, then stirred at 60°C with water (300 ml) and concentrated hydrochloric acid (20 ml), the aqueous layer having a pH of 3 or less.
  • the organic layer is separated, then stirred with water (300 ml) at 60°C for 15 minutes and the organic layer separated. This is repeated until the aqueous layer has a pH between 6 and 8.
  • the solvent is removed in vacuo at 90°C, and the residual oil is distilled at 1.33 to 2.66 mbar under high vacuum to yield in the appropriate fractions of 1-(3,4- dichlorophenyl)cyclobutyl cyanide.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Physical Or Chemical Processes And Apparatus (AREA)
  • Crystals, And After-Treatments Of Crystals (AREA)
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PCT/EP1996/005246 1995-12-02 1996-11-28 Process for the preparation of 1-aryl-1-cyanocyclobutane derivatives WO1997020810A1 (en)

Priority Applications (17)

Application Number Priority Date Filing Date Title
AU10939/97A AU717603B2 (en) 1995-12-02 1996-11-28 Process for the preparation of 1-aryl-1-cyanocyclobutane derivatives
PL96326926A PL185047B1 (pl) 1995-12-02 1996-11-28 Sposób wytwarzania pochodnych arylocyklobutylonitryli
IL12434196A IL124341A (en) 1995-12-02 1996-11-28 Process for the preparation of a history of 1-aryl - 1 cyanocyclobutane
EP96941602A EP0863868B1 (en) 1995-12-02 1996-11-28 Process for the preparation of 1-aryl-1-cyanocyclobutane derivatives
US09/077,698 US6545173B1 (en) 1995-12-02 1996-11-28 Process for the preparation of 1-aryl-1-cyanocyclobutane derivatives
KR1019980704120A KR19990071838A (ko) 1995-12-02 1996-11-28 1-아릴-1-시아노시클로부탄 유도체의 제조 방법
DK96941602T DK0863868T3 (da) 1995-12-02 1996-11-28 Fremgangsmåde til fremstilling af 1-aryl-1-cyanocyclobutanderivater
BR9611683A BR9611683A (pt) 1995-12-02 1996-11-28 Processo para a preparação de compostos
NZ323896A NZ323896A (en) 1995-12-02 1996-11-28 Process for the preparation of 1-aryl-1-cyanocyclobutane derivatives
SI9630254T SI0863868T1 (en) 1995-12-02 1996-11-28 Process for the preparation of 1-aryl-1-cyanocyclobutane derivatives
AT96941602T ATE199247T1 (de) 1995-12-02 1996-11-28 Verfahren zur herstellung von 1-aryl-1- cyanocyclobutan-derivaten
SK626-98A SK282470B6 (sk) 1995-12-02 1996-11-28 Spôsob prípravy derivátov 1-aryl-1-kyanocyklobutánu
DE69611835T DE69611835T2 (de) 1995-12-02 1996-11-28 Verfahren zur herstellung von 1-aryl-1-cyanocyclobutan-derivaten
JP9520945A JP2000501402A (ja) 1995-12-02 1996-11-28 １―アリール―１―シアノシクロブタン誘導体の製法
BG102473A BG63498B1 (bg) 1995-12-02 1998-05-21 Метод за получаване на производни на 1-арил-1-цианоциклобутан
NO982474A NO309265B1 (no) 1995-12-02 1998-05-29 Fremgangsmåte for fremstilling av 1-aryl-1-cyanocyklobutan- derivater
GR20010400419T GR3035572T3 (en) 1995-12-02 2001-03-13 Process for the preparation of 1-aryl-1-cyanocyclobutane derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9524681.5A GB9524681D0 (en) 1995-12-02 1995-12-02 Chemical process
GB9524681.5 1995-12-02

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WO1997020810A1 true WO1997020810A1 (en) 1997-06-12
WO1997020810A8 WO1997020810A8 (en) 2000-10-05

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US (1) US6545173B1 (pt)
EP (1) EP0863868B1 (pt)
JP (1) JP2000501402A (pt)
KR (1) KR19990071838A (pt)
CN (1) CN1075057C (pt)
AT (1) ATE199247T1 (pt)
AU (1) AU717603B2 (pt)
BG (1) BG63498B1 (pt)
BR (1) BR9611683A (pt)
CA (1) CA2235043A1 (pt)
CZ (1) CZ164798A3 (pt)
DE (1) DE69611835T2 (pt)
DK (1) DK0863868T3 (pt)
ES (1) ES2154848T3 (pt)
GB (1) GB9524681D0 (pt)
GR (1) GR3035572T3 (pt)
HU (1) HUP9903481A3 (pt)
IL (1) IL124341A (pt)
MX (1) MX9804022A (pt)
NO (1) NO309265B1 (pt)
NZ (1) NZ323896A (pt)
PL (1) PL185047B1 (pt)
PT (1) PT863868E (pt)
RU (1) RU2179168C2 (pt)
SI (1) SI0863868T1 (pt)
SK (1) SK282470B6 (pt)
TR (1) TR199800987T2 (pt)
WO (1) WO1997020810A1 (pt)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6331571B1 (en) 1998-08-24 2001-12-18 Sepracor, Inc. Methods of treating and preventing attention deficit disorders
US6339106B1 (en) 1999-08-11 2002-01-15 Sepracor, Inc. Methods and compositions for the treatment and prevention of sexual dysfunction
US6399826B1 (en) 1999-08-11 2002-06-04 Sepracor Inc. Salts of sibutramine metabolites, methods of making sibutramine metabolites and intermediates useful in the same, and methods of treating pain
EP1238967A1 (en) * 2001-02-28 2002-09-11 Council of Scientific and Industrial Research A process for the preparation of 1-(cyano(aryl)methyl) cyclohexanol
US6476078B2 (en) 1999-08-11 2002-11-05 Sepracor, Inc. Methods of using sibutramine metabolites in combination with a phosphodiesterase inhibitor to treat sexual dysfunction
US6504044B2 (en) 2001-02-28 2003-01-07 Council Of Scientific And Industrial Research Process for the preparation of 1-[cyano(aryl)methyl] cyclohexanol
US6610887B2 (en) 2001-04-13 2003-08-26 Sepracor Inc. Methods of preparing didesmethylsibutramine and other sibutramine derivatives
US6974838B2 (en) 1998-08-24 2005-12-13 Sepracor Inc. Methods of treating or preventing pain using sibutramine metabolites
AT503354B1 (de) * 2006-02-22 2008-07-15 Dsm Fine Chem Austria Gmbh Verfahren zur herstellung von 3,4-disubstituierten phenylessigsäuren, sowie neue zwischenverbindungen

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CZ300903B6 (cs) * 2008-06-09 2009-09-09 Lucební závody Draslovka a. s. Kolín Zpusob výroby cykloalkankarbonitrilu

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MAKOSZA, MIECZYSLAW ET AL: "Reactions of organic anions. VI. Catalytic alkylation of phenylacetonitrile with alkyl dihalides in aqueous medium", ROCZ. CHEM. (1966), 40(10), 1647-55 CODEN: ROCHAC, 1966, XP000617213 *
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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6331571B1 (en) 1998-08-24 2001-12-18 Sepracor, Inc. Methods of treating and preventing attention deficit disorders
US7071234B2 (en) 1998-08-24 2006-07-04 Sepracor Inc. Methods of treating or preventing erectile dysfunction
US6538034B2 (en) 1998-08-24 2003-03-25 Thomas P. Jerussi Methods of treating or preventing weight gain, obesity, and related disorders
US6974838B2 (en) 1998-08-24 2005-12-13 Sepracor Inc. Methods of treating or preventing pain using sibutramine metabolites
US6974837B2 (en) 1999-08-11 2005-12-13 Sepracor Inc. Compositions comprising sibutramine metabolites in combination with phosphodiesterase inhibitors
US6339106B1 (en) 1999-08-11 2002-01-15 Sepracor, Inc. Methods and compositions for the treatment and prevention of sexual dysfunction
US6399826B1 (en) 1999-08-11 2002-06-04 Sepracor Inc. Salts of sibutramine metabolites, methods of making sibutramine metabolites and intermediates useful in the same, and methods of treating pain
US6476078B2 (en) 1999-08-11 2002-11-05 Sepracor, Inc. Methods of using sibutramine metabolites in combination with a phosphodiesterase inhibitor to treat sexual dysfunction
US6710087B2 (en) 1999-08-11 2004-03-23 Sepracor, Inc. Methods of treating or preventing neuropathic pain using sibutramine metabolites
EP1238967A1 (en) * 2001-02-28 2002-09-11 Council of Scientific and Industrial Research A process for the preparation of 1-(cyano(aryl)methyl) cyclohexanol
US6504044B2 (en) 2001-02-28 2003-01-07 Council Of Scientific And Industrial Research Process for the preparation of 1-[cyano(aryl)methyl] cyclohexanol
US6894189B2 (en) 2001-04-13 2005-05-17 Sepracor Inc. Methods of preparing didesmethylsibutramine and other sibutramine derivatives
US6610887B2 (en) 2001-04-13 2003-08-26 Sepracor Inc. Methods of preparing didesmethylsibutramine and other sibutramine derivatives
AT503354B1 (de) * 2006-02-22 2008-07-15 Dsm Fine Chem Austria Gmbh Verfahren zur herstellung von 3,4-disubstituierten phenylessigsäuren, sowie neue zwischenverbindungen

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AU1093997A (en) 1997-06-27
PL185047B1 (pl) 2003-02-28
EP0863868B1 (en) 2001-02-21
WO1997020810A8 (en) 2000-10-05
SK62698A3 (en) 1999-02-11
EP0863868A1 (en) 1998-09-16
CZ164798A3 (cs) 1998-09-16
SI0863868T1 (en) 2001-06-30
MX9804022A (es) 1998-09-30
IL124341A (en) 2001-09-13
NZ323896A (en) 2000-01-28
CA2235043A1 (en) 1997-06-12
JP2000501402A (ja) 2000-02-08
PT863868E (pt) 2001-06-29
NO982474D0 (no) 1998-05-29
RU2179168C2 (ru) 2002-02-10
GR3035572T3 (en) 2001-06-29
KR19990071838A (ko) 1999-09-27
DK0863868T3 (da) 2001-03-19
NO309265B1 (no) 2001-01-08
CN1203585A (zh) 1998-12-30
US6545173B1 (en) 2003-04-08
SK282470B6 (sk) 2002-02-05
HUP9903481A3 (en) 2001-11-28
BR9611683A (pt) 1999-03-02
ATE199247T1 (de) 2001-03-15
BG63498B1 (bg) 2002-03-29
BG102473A (en) 1999-05-31
GB9524681D0 (en) 1996-01-31
PL326926A1 (en) 1998-11-09
HUP9903481A1 (hu) 2001-01-29
DE69611835T2 (de) 2001-06-07
CN1075057C (zh) 2001-11-21
ES2154848T3 (es) 2001-04-16
IL124341A0 (en) 1998-12-06
DE69611835D1 (de) 2001-03-29
NO982474L (no) 1998-05-29
TR199800987T2 (xx) 1998-09-21
AU717603B2 (en) 2000-03-30

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